PROJECT SUMMARY/ABSTRACT The majority of patients with multiple myeloma (MM) ultimately die of progressive disease despite high rates of initial response to novel agents. While complete response (CR) is achievable in a significant subset of patients, most of these individuals relapse as a consequence of minimal residual disease (MRD) defined by occult foci of treatment insensitive tumor cells clones. High dose chemotherapy followed by autologous stem cell transplantation (ASCT) improves response, but relapse remains virtually inevitable. No modification to high dose melphalan chemotherapy conditioning regimens has further augmented the impact of ASCT on outcome over the past two decades. Unmodified CD38 monoclonal antibodies (MAbs) have demonstrated anti-MM tumor cell responses and CD38 antigen targeting with ?-emitter radioimmunotherapy (RIT) can eliminate disease in pre-clinical MM models. In clinical settings however, ?-emitter RIT has been associated with dose limiting toxicity that can prevent dose escalation to levels necessary for elimination of MRD in a substantial proportion of patients. Based on the physical characteristics of ?-emitting radionuclides and new opportunities to harness their potential, there is a compelling rationale for employing ?-emitter RIT to treat MM. The ?-emitter 211At deposits a very large amount of energy (~100 keV/?m) within a few cell diameters (50-90 ?m) resulting in irreparable double strand DNA breaks that overwhelm cellular repair mechanisms. We anticipate that this combination of high energy and short path length will confer a unique capacity to kill individual targeted MM cells and eliminate MRD with minimal radiation damage to surrounding tissues. This proposal will use 211At to functionalize an anti-CD38 monoclonal antibody ([211At]OKT10-B10) as part of a novel approach to ASCT conditioning. The goal of this project is to address three hypotheses: 1). [211At]OKT10-B10 will eliminate MRD by selectively targeting all malignant plasma cells irrespective of mutational status, 2). [211At]OKT10-B10 will disrupt the disease permissive milieu found in the bone marrow microenvironment of MM patients and 3) [211At]OKT10-B10 will demonstrate a therapeutic index sufficient to safely sterilize all occult sites of disease. First, we will generate clinical grade [211At]OKT10-B10 necessary to perform patient studies. Second, we will conduct a clinical trial to a) demonstrate that [211At]OKT10-B10 localizes to MM target cells as confirmed by direct measurement of 211At in the bone marrow and alpha camera images of target tissue; and b) evaluate the safely of [211At]OKT10-B10 dose escalation in combination with high dose melphalan. Third, we will assess the impact of [211At]OKT10-B10 on a) stringent complete response rates, b) MRD detected by high throughput next generation sequencing and multi-parameter high sensitivity flow cytometry, c) the bone marrow microenvironment, d) MM cell repopulating potential in a SCID-hu model, and e) double strand DNA injury in target cells. The successful elimination of MRD through the incorporation of [211At]OKT10-B10 into ASCT conditioning could lead to significant improvements in MM patient survival and potentially eradicate disease.